Functional inactivation of menin, encoded by the MEN1 gene, causes the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome and some but not all sporadic parathyroid and pancreatic endocrine tumors. Additional genes for these conditions can be identified with the help of exome and genome sequencing approaches. Another approach, from unraveling molecular events upstream or downstream of menin, could point to other causative genes and/or regulatory events responsible for such tumor types. Menin resides in a histone methylating protein complex that trimethylates histone H3 at lysine-4 (H3K4me3), an epigenetic mark for active gene expression. Therefore, we have determined a genome-wide map of menin-dependent H3K4me3 (using ChIP-Seq) and menin-dependent gene-expression program in wild-type (WT) and menin-null mouse embryonic stem cells (ESCs) and in pancreatic islet-like endocrine cells (PILECs), which we derived from WT and menin-null mouse ESCs through in vitro differentiation. We found menin-dependent H3K4me3 specifically targeting the Meg3 gene in mouse ESCs, and all four Hox loci in differentiated PILECs. Gene expression from the Meg3 locus and from all four Hox loci was abolished in menin-null cells. Both Meg3 and Hox loci have been implicated in MEN1-like sporadic tumors: MEG3 in pituitary tumors, and HOX in parathyroid tumors. Our data suggest that these genes with menin-dependent H3K4me3 could be relevant players in the tumorigenesis of endocrine cell types associated with MEN1. Furthermore, our work shows that menin-null mouse ESCs could also be differentiated in vitro into islet-like endocrine cells, underscoring the utility of menin-null ESC-derived specialized cell types for genome-wide analyses studies. MEG3 is a tumor suppressor long non-coding RNA. We showed that menins tumor suppressor activity is elicited by epigenetic up-regulation of MEG3 which leads to down-regulation of a target of MEG3, a proto-oncogene (c-MET). We also found a reciprocal correlation of MEG3 (low) and c-MET (high) levels in human MEN1-associated and sporadic insulinomas. Understanding the regulation and activity of c-MET, and genes at the MEG3 and HOX loci would be useful to gain insights into the role of menin as a tumor suppressor in endocrine tumors. We have shown in MIN6 cells by using Meg3-ChIRP-Seq and Meg3-ChIRP-PCR that at least four distinct c-Met genomic regions are occupied by Meg3. These regions in and near the c-Met gene show enhancer-specific histone modifications in the absence of Meg3 to promote c-Met transcription. In the presence of Meg3, repressive histone modifications at the same regions silence c-Met gene expression. Therefore, targeting MEG3 and associated epigenetic marks at these genomic regions could be useful to modulate the expression of c-MET in the management of endocrine tumors. Genetically engineered mouse models with tissue-specific deletions of Meg3 or c-Met in combination with Men1 deletion will be useful to establish the role of these genes in endocrine neoplasia. One of the main endocrine tumor type associated with the MEN1 syndrome is parathyroid adenoma that causes primary hyperparathyroidism (PHPT). This tumor can also occur sporadically, and 35% of such tumors have somatic MEN1 mutations. Furthermore, parathyroid tumors can occur in an isolated familial form with no other syndromic features, known as familial isolated primary hyperparathyroidism (FIHP). Using an exome sequencing approach, we have identified germline variants in the GCM2 gene in 18% of our FIHP families. These variants are localized in a 20 amino acid C-terminal conserved inhibitory domain (CCID), and in reporter assays GCM2 protein with these variants shows enhanced transcriptional activity compared to normal GCM2 protein. Among these variants, we found an ethnicity specific GCM2 germline variant (p.Y394S) in Ashkenazi Jewish kindreds with FIHP. GCM2 is a master regulator of parathyroid gland development. We are interested in investigating the mechanism by which GCM2 activating mutations cause parathyroid tumors, and whether other mechanisms exist that can lead to the activation of GCM2 for parathyroid tumor formation. Genetically engineered mouse models with FIHP-associated germline heterozygous Gcm2 mutations will be useful to establish the role of GCM2 in parathyroid neoplasia. We are also investigating the molecular basis of highly enhanced transcriptional activity of GCM2 upon deletion of the CCID. In order to study the mechanisms that lead to parathyroid tumors, we are establishing primary cell cultures of human or mouse parathyroid glands, and subsequent derivation of parathyroid cell lines. Such model systems can be valuable to investigate the genes and pathways associated with normal and abnormal proliferation and function of parathyroid glands. Another tumor associated with the MEN1 syndrome is lipoma. This is a benign tumor usually only removed for cosmetic reasons. Therefore, studying this tumor of fat cells (adipocytes) is challenging due to the non-availability of tumor specimens from human MEN1 patients or from the mouse model of this disease. We used a novel approach to study lipoma cells by using in vitro differentiation to derive normal and menin-deficient adipocytes. We found a novel association of menin in the regulation of adipocyte size because menin-deficient adipocytes were larger. By gene expression microarray analysis, we found novel targets of menin: differentially methylated genes including MEG3, and the mouse prolactin gene family locus. Our findings support a role for menin in the regulation of: adipocyte size, differential DNA methylation and coordinately expressed genes in gene clusters. We have shown that cyclin-dependent kinase inhibitors (CDKIs) of the INK4 family (4 genes) and the Cip/Kip family (3 genes) that negatively regulate cell cycle progression and cell proliferation have rare germline or somatic mutations in endocrine tumor states related to MEN1. Also, mouse models show an endocrine neoplasia phenotype in 'knock-in' mice homozygous for the CDK4-R24C mutation, or by the combined loss of two different CDKIs, p18 and p27. Therefore, understanding the molecular basis of CDK and CDKI regulation could provide insights into their contribution to endocrine tumorigenesis. We have investigated the contribution of cell cycle regulators in endocrine tumorigenesis, particularly mutations in CDKI genes. We are interested in investigating the molecular basis of cell cycle regulation in endocrine cells.